Vitamin B1 (thiamine) and dementia

Abstract

The earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine (vitamin B1). Throughout the last century, research showed that thiamine deficiency is associated with neurological problems, including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer's disease (AD) in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients and by thiamine decline, and a decrease in their levels could account for the reduction in glucose metabolism. In preclinical models, reduced thiamine can drive AD-like abnormalities, including memory deficits, neuritic plaques, and hyperphosphorylation of tau. Furthermore, excess thiamine diminishes AD-like pathologies. In addition to dietary deficits, drugs or other manipulations that interfere with thiamine absorption can cause thiamine deficiency. Elucidating the reasons why the brains of AD patients are functionally thiamine deficient and determining the effects of thiamine restoration may provide critical information to help treat patients with AD.

Keywords: Alzheimer's disease; glucose metabolism; mitochondria; thiamine; vitamin B1.

Figure 1

Similarities between memory deficits in Alzheimer’s disease (AD) and in thiamine deficiency in humans. Performance on a large number of cognitive tasks was compared in controls, Korsakoff syndrome (KS) patients, and AD patients. Performance on only three tasks are shown. Performance on each task declines similarly in patients with AD and those who are thiamine deficient (KS patients).

Figure 2

Role of thiamine in brain glucose metabolism for energy utilization and neurotransmitter synthesis. Like in other tissues, glucose metabolism in the brain uses thiamine-dependent enzymes at critical steps. The brain uses ten times its body mass in glucose compared to the whole body. Thiamine-dependent enzymes (noted by ***) are situated in key steps of glucose metabolism: transketolase in the pentose shunt, pyruvate dehydrogenase as a link between glycolysis and the tricarboxylic acid (TCA) cycle, and KGDHC in the TCA cycle. Brain glucose also provides the carbon for synthesis of multiple neurotransmitters, including glutamate and acetylcholine, which are important in AD. The cognitive enhancers used in AD target the neurotransmitters acetylcholine and glutamate. Normal metabolism also results in production of reactive oxygen species (ROS), which contribute to tissue damage, including neuropathy in diabetes.

Figure 3

Cell-specific increases in markers of inflammation and oxidative stress occur in thiamine deficiency. Mice were made thiamine deficient and the brains were then analyzed for markers of inflammation and oxidative stress. Similar increases in these same variables have been observed in brains from AD patients at autopsy. In the animal model, the temporal response in each cell type was determined. Shown is the approximate order of appearance of the stressor within each cell type with thiamine deficiency, and the increases within each cell type are listed in the order of response. The endothelial cell response is first and blockade of endothelial responses protect against neuronal loss.^,

Figure 4

Thiamine deficiency accelerates deposition of thioflavin S–positive amyloid plaque. Mice were made thiamine deficient (TD) for 10 days, and the number of thioflavin S–positive plaques were determined throughout the brain. The graph shows the percent area occupied by plaques quantified from the cortex, hippocampus, and thalamus. Data represent the means ± SEM (control, n = 9; TD, n = 10) from 2–3 independent experiments.